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Density-functional Theory in Drug Design – the Chemistry of the Anti-tumor Drug Cisplatin and Photoactive Psoralen Compounds
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
2003 In: Quantum Medicinal Chemistry, 2003, 113-153 p.Chapter in book (Other academic) Published
Place, publisher, year, edition, pages
2003. 113-153 p.
URN: urn:nbn:se:uu:diva-95776ISBN: 3-527-30456-8OAI: oai:DiVA.org:uu-95776DiVA: diva2:170113
Available from: 2007-04-20 Created: 2007-04-20Bibliographically approved
In thesis
1. Quantum Chemical Studies of Chemotherapeutic Drug Cisplatin: Activation and Binding to DNA
Open this publication in new window or tab >>Quantum Chemical Studies of Chemotherapeutic Drug Cisplatin: Activation and Binding to DNA
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The serendipitous discovery of the potent cytotoxic properties of cisplatin brought about a revolution in the treatment of certain types of cancer, but almost fifty years later, there still remain unknown areas in the chemistry of cisplatin. There are questions regarding which form of the drug reaches its DNA target, or why certain DNA sequences are more preferred than others for reaction with cisplatin. The work presented here aims to address some of these problems, using quantum chemical calculations to complement and interpret available experimental data.

Cisplatin's activation reactions are explored by Density Functional Theory (DFT) on two model systems, one solely using a self-consistent reaction field (SCRF) for modeling bulk water, and one including an additional partial solvation shell of water molecules. It is concluded that adding explicit solvation provides a better picture than using SCRF solvation alone. The energy surface supports the view that the active form of cisplatin is the monoaquated form.

The activation reactions of the cisplatin-derived drug, JM118, are investigated using DFT and SCRF calculations using three solvation model systems. The results show a slower rate of hydrolysis for the first reaction, and a faster rate for the second, suggesting diaquated JM118 as the main DNA binding form of the drug.

Diaquated cisplatin's first and second reaction with guanine and adenine are studied using DFT and SCRF solvation. Cisplatin's propensity toward guanine in the first substitution is explained by larger stabilisation energy for the initially formed complex and by favoured kinetics. For the second substitution, higher stability in complexation with guanine over adenine is ascribed as the main factor favouring guanine over adenine substitution. This provides the first explanation for the predominance of 1,2-d(GpG) over 1,2-d(ApG) adducts, and the direction specificity of the 1,2-d(ApG) adducts.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 74 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 295
Quantum chemistry, cisplatin, quantum chemistry, DNA, density functional theory, activation, JM118, substitution reaction, Platinum, guanine, adenine, cytostatic drug, aquation, anation, activation, Kvantkemi
urn:nbn:se:uu:diva-7824 (URN)978-91-554-6868-2 (ISBN)
Public defence
2007-05-11, B42, BMC, Husargatan 3, Uppsala, 13:15
Available from: 2007-04-20 Created: 2007-04-20Bibliographically approved

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